The effect of diazoxide upon heat shock protein expression and physiological response to hemorrhagic shock and cerebral stroke /

by O'Sullivan, Joseph C

Abstract (Summary)

THE EFFECT OF DIAZOXIDE UPON HEAT SHOCK PROTEIN EXPRESSION AND
PHYSIOLOGICAL RESPONSE TO HEMORRHAGIC SHOCK AND CEREBRAL STROKE
LTC Joseph C. O’Sullivan
Thesis directed by: Joseph T. McCabe, Ph.D., Professor and Vice-Chair of the
Department of Anatomy, Physiology and Genetics; and Professor of Neuroscience and
Molecular and Cell Biology
Our team tested the hypothesis that pharmacological induction of ischemic
preconditioning (IPC) can offer cytoprotection and preserve vital tissues after cerebral
stroke with hemorrhagic shock. The compound, diazoxide (DZ), is known to mimic IPC
through its effects as a mitochondrial KATP channel opener and succinate dehydrogenase
inhibitor. The effect of DZ was examined under two IPC protocols: delayed
preconditioning and postconditioning in an anesthetized rat model of hemorrhagic shock,
combined in some experimental groups with cerebral vascular occlusion (stroke).
When DZ was administered 24 hours prior to shock (delayed preconditioning), it
significantly reduced hyperglycemia, which in vehicle-treated animals persisted after
resuscitation. DZ also attenuated hyperlactatemia during the 1 hour shock period. With
more severe trauma from combined stroke and shock, DZ also decreased hyperglycemia,
but the apparent reduction of hyperlactatemia did not reach statistical significance. DZ
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also appeared to increase the survival rate of animals that sustained combined stroke and
shock, but not significantly (p=.058). The expression levels of heat shock proteins 25
(HSP25) and 70 (HSP70) were used as biomarkers for assessing the response of the
kidney, liver, and right cerebral cortex and hippocampus to combined stroke and shock.
Compared to vehicle-treated animals, DZ- pretreated rats subjected to stroke and shock
exhibited increased HSP25 and HSP70 expression in kidney, liver and brain tissue.
When administered in a postconditioning Stroke + Shock model, where DZ was
administered at two time points after stroke and shock, DZ again caused a significant
increase in HSP25 and HSP70 expression in the ipsilateral cerebral cortex and
hippocampus. As a postconditioning trigger, given after stroke and shock, DZ was
effective when it was administered 60 minutes after shock immediately prior to
reperfusion but not when given 10 minutes after Stroke and Shock (without immediate
reperfusion). Taken together, these results suggest DZ attenuates physiological indicators
of metabolic stress following shock or combined shock and stroke, that it may increase
survivability, and that it enhances the upregulation of cytoprotective heat shock protein
expression in key organs.
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